**Background:** Glaucoma is a leading cause of irreversible blindness worldwide, characterized by progressive loss of retinal ganglion cells (RGCs) and optic nerve atrophy. While elevated intraocular pressure (IOP) is the major risk factor, it does not fully explain all cases, particularly normal-tension glaucoma (NTG). Recent research has identified additional pathomechanisms including vascular dysfunction, oxidative stress, neuroinflammation, and autoimmune imbalances. This narrative review aims to summarize the current understanding of glaucomatous etiopathogenesis and explore immunomodulatory and antioxidant therapeutic strategies.
**Methods:** The authors conducted a narrative review of the literature, synthesizing evidence from preclinical studies, clinical trials, and epidemiological investigations. They examined the pathophysiology of glaucoma, focusing on oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, neuroinflammation, and autoimmune factors. They then reviewed emerging immunomodulatory and antioxidant drug candidates, including Fas ligand inhibitors, adenosine receptor modulators, biologics, complement inhibitors, phosphodiesterase inhibitors, antibiotics, stem cell therapies, and various natural and synthetic antioxidants.
**Key Results:** The review highlights several promising immunomodulatory candidates. ONL1204, a small peptide inhibitor of the Fas receptor, suppressed RGC apoptosis and neuroinflammation in a murine glaucoma model, and a clinical trial (NCT05160805) is underway. Adenosine A2A receptor antagonists like SCH 58261 and caffeine reduced neuroinflammation and preserved RGCs in animal models. The biologic etanercept, a TNF-α receptor antagonist, inhibited glial activation and preserved RGCs in a murine model. Complement inhibition with an anti-C5 antibody reduced RGC loss in an experimental autoimmune glaucoma model. Ibudilast, a PDE4 inhibitor, mitigated neuroinflammation and improved RGC viability in a rodent model. Minocycline and azithromycin demonstrated neuroprotective effects by suppressing proapoptotic cascades and reducing neuroinflammation. Among antioxidants, nicotinamide (vitamin B3) improved inner retinal function in a randomized controlled trial of 57 glaucoma patients. Astaxanthin, resveratrol, α-lipoic acid, curcumin, and flavonoids from Ginkgo biloba showed neuroprotective effects in preclinical models. Valproic acid improved visual acuity in advanced glaucoma patients in a clinical trial. N-acetylcysteine attenuated retinal oxidative stress in rodent models. NOX inhibitors like GKT137831 and GLX7013114 reduced retinal inflammation and glial activation. ROCK inhibitors such as Y-27632 and ripasudil showed potential by reducing IOP and oxidative stress.
**Clinical Implications:** The review underscores the potential of immunomodulatory and antioxidant therapies to complement existing IOP-lowering treatments by targeting alternative pathomechanisms. These strategies could be particularly beneficial for patients with NTG or those who continue to progress despite adequate IOP control. However, challenges remain, including the need to balance pro- and anti-inflammatory signals, ensure drug bioavailability, and conduct rigorous clinical trials with appropriate biomarkers and long-term follow-up. The authors conclude that further research is necessary to translate these preclinical findings into effective clinical therapies.